US4877794A - 2-Alkoxy-n-(1-azabicyclo(2.2.2)oct-3-yl) benzamide and thiobenzamide compositions and the use thereof to treat schizophrenia - Google Patents
2-Alkoxy-n-(1-azabicyclo(2.2.2)oct-3-yl) benzamide and thiobenzamide compositions and the use thereof to treat schizophrenia Download PDFInfo
- Publication number
- US4877794A US4877794A US07/240,868 US24086888A US4877794A US 4877794 A US4877794 A US 4877794A US 24086888 A US24086888 A US 24086888A US 4877794 A US4877794 A US 4877794A
- Authority
- US
- United States
- Prior art keywords
- azabicyclo
- oct
- amino
- dopamine
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 201000000980 schizophrenia Diseases 0.000 title claims description 9
- 239000000203 mixture Substances 0.000 title description 23
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 title description 6
- QIOZLISABUUKJY-UHFFFAOYSA-N Thiobenzamide Chemical compound NC(=S)C1=CC=CC=C1 QIOZLISABUUKJY-UHFFFAOYSA-N 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 239000002253 acid Substances 0.000 claims abstract description 10
- -1 amino, methylamino Chemical group 0.000 claims abstract description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- 239000001301 oxygen Substances 0.000 claims abstract description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000005864 Sulphur Chemical group 0.000 claims abstract description 4
- 125000001475 halogen functional group Chemical group 0.000 claims abstract description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 43
- 238000000034 method Methods 0.000 claims description 24
- 241001465754 Metazoa Species 0.000 claims description 9
- FEROPKNOYKURCJ-UHFFFAOYSA-N 4-amino-N-(1-azabicyclo[2.2.2]octan-3-yl)-5-chloro-2-methoxybenzamide Chemical compound COC1=CC(N)=C(Cl)C=C1C(=O)NC1C(CC2)CCN2C1 FEROPKNOYKURCJ-UHFFFAOYSA-N 0.000 claims description 4
- 230000037396 body weight Effects 0.000 claims description 4
- DYMNHNMNXIHEHH-UHFFFAOYSA-N n-(1-azabicyclo[2.2.2]octan-3-yl)-5-chloro-2-methoxy-4-(methylamino)benzamide Chemical compound C1=C(Cl)C(NC)=CC(OC)=C1C(=O)NC1C(CC2)CCN2C1 DYMNHNMNXIHEHH-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- IFHYLWUYSSUTLG-UHFFFAOYSA-N n-(1-azabicyclo[2.2.2]octan-3-yl)-2,4-dimethoxybenzamide Chemical compound COC1=CC(OC)=CC=C1C(=O)NC1C(CC2)CCN2C1 IFHYLWUYSSUTLG-UHFFFAOYSA-N 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 241000282414 Homo sapiens Species 0.000 claims description 2
- RJKGVLCGKNHLDY-UHFFFAOYSA-N n-(1-azabicyclo[2.2.2]octan-3-yl)-2-methoxybenzamide Chemical compound COC1=CC=CC=C1C(=O)NC1C(CC2)CCN2C1 RJKGVLCGKNHLDY-UHFFFAOYSA-N 0.000 claims description 2
- 101150108015 STR6 gene Proteins 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- ICJNSKXWIYJRPS-UHFFFAOYSA-N n-(1-azabicyclo[2.2.2]octan-3-yl)-2-propoxybenzamide Chemical compound CCCOC1=CC=CC=C1C(=O)NC1C(CC2)CCN2C1 ICJNSKXWIYJRPS-UHFFFAOYSA-N 0.000 claims 1
- 229940054066 benzamide antipsychotics Drugs 0.000 abstract description 9
- 150000003936 benzamides Chemical class 0.000 abstract description 8
- 230000002932 anti-schizophrenic effect Effects 0.000 abstract description 6
- 125000003545 alkoxy group Chemical group 0.000 abstract description 2
- 150000002431 hydrogen Chemical group 0.000 abstract description 2
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 abstract 1
- 101150035983 str1 gene Proteins 0.000 abstract 1
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 34
- 229960003638 dopamine Drugs 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 21
- 208000013403 hyperactivity Diseases 0.000 description 21
- 239000007787 solid Substances 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- PLDUPXSUYLZYBN-UHFFFAOYSA-N Fluphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 PLDUPXSUYLZYBN-UHFFFAOYSA-N 0.000 description 16
- 229960002690 fluphenazine Drugs 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 241000700159 Rattus Species 0.000 description 13
- REUAXQZIRFXQML-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-3-amine Chemical compound C1CC2C(N)CN1CC2 REUAXQZIRFXQML-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 11
- 239000012458 free base Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 229940125904 compound 1 Drugs 0.000 description 9
- 238000001802 infusion Methods 0.000 description 9
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 210000001009 nucleus accumben Anatomy 0.000 description 8
- 239000001530 fumaric acid Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 230000008485 antagonism Effects 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 230000003474 anti-emetic effect Effects 0.000 description 5
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000001569 carbon dioxide Substances 0.000 description 4
- 229910002092 carbon dioxide Inorganic materials 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 239000003176 neuroleptic agent Substances 0.000 description 4
- 230000000701 neuroleptic effect Effects 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 230000003542 behavioural effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 235000011167 hydrochloric acid Nutrition 0.000 description 3
- 238000002513 implantation Methods 0.000 description 3
- RHMQNXNXUZLEIY-UHFFFAOYSA-N methanol;2-propan-2-yloxypropane Chemical compound OC.CC(C)OC(C)C RHMQNXNXUZLEIY-UHFFFAOYSA-N 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229910001220 stainless steel Inorganic materials 0.000 description 3
- 239000010935 stainless steel Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 229960004940 sulpiride Drugs 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- BGRJTUBHPOOWDU-NSHDSACASA-N (S)-(-)-sulpiride Chemical compound CCN1CCC[C@H]1CNC(=O)C1=CC(S(N)(=O)=O)=CC=C1OC BGRJTUBHPOOWDU-NSHDSACASA-N 0.000 description 2
- STZHBULOYDCZET-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-3-amine;hydron;dichloride Chemical compound Cl.Cl.C1CC2C(N)CN1CC2 STZHBULOYDCZET-UHFFFAOYSA-N 0.000 description 2
- GPVDHNVGGIAOQT-UHFFFAOYSA-N 2,4-dimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C(OC)=C1 GPVDHNVGGIAOQT-UHFFFAOYSA-N 0.000 description 2
- KVIUXRJCBBXEGJ-UHFFFAOYSA-N 2,4-dimethoxybenzoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C(OC)=C1 KVIUXRJCBBXEGJ-UHFFFAOYSA-N 0.000 description 2
- PBIUDEUWYGBHDW-UHFFFAOYSA-N 2-chloro-1-pyridin-3-ylethanone;hydrochloride Chemical compound Cl.ClCC(=O)C1=CC=CN=C1 PBIUDEUWYGBHDW-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229920005439 Perspex® Polymers 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000002111 antiemetic agent Substances 0.000 description 2
- 229940125683 antiemetic agent Drugs 0.000 description 2
- 230000000949 anxiolytic effect Effects 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000006742 locomotor activity Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- MVKDKUUCCOPJSG-UHFFFAOYSA-N n-(1-azabicyclo[2.2.2]octan-3-yl)benzamide Chemical class C1N(CC2)CCC2C1NC(=O)C1=CC=CC=C1 MVKDKUUCCOPJSG-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000004926 polymethyl methacrylate Substances 0.000 description 2
- DPLVEEXVKBWGHE-UHFFFAOYSA-N potassium sulfide Chemical compound [S-2].[K+].[K+] DPLVEEXVKBWGHE-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- YICLZXLNGYAYHW-UHFFFAOYSA-N (2,4-dimethoxyphenyl)-(1h-imidazol-2-yl)methanone Chemical compound COC1=CC(OC)=CC=C1C(=O)C1=NC=CN1 YICLZXLNGYAYHW-UHFFFAOYSA-N 0.000 description 1
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- RZNHSEZOLFEFGB-UHFFFAOYSA-N 2-methoxybenzoyl chloride Chemical compound COC1=CC=CC=C1C(Cl)=O RZNHSEZOLFEFGB-UHFFFAOYSA-N 0.000 description 1
- VFJOJJWSUHOTSF-UHFFFAOYSA-N 3-methoxynaphthalene-2-carbonyl chloride Chemical compound C1=CC=C2C=C(C(Cl)=O)C(OC)=CC2=C1 VFJOJJWSUHOTSF-UHFFFAOYSA-N 0.000 description 1
- VFMOALNFJXDNSO-UHFFFAOYSA-N 4-amino-3-chloro-5-(trifluoromethyl)benzoyl chloride Chemical compound NC1=C(Cl)C=C(C(Cl)=O)C=C1C(F)(F)F VFMOALNFJXDNSO-UHFFFAOYSA-N 0.000 description 1
- RVEATKYEARPWRE-UHFFFAOYSA-N 4-amino-5-chloro-2-methoxybenzoic acid Chemical compound COC1=CC(N)=C(Cl)C=C1C(O)=O RVEATKYEARPWRE-UHFFFAOYSA-N 0.000 description 1
- UVJOFJBHOZFKQM-UHFFFAOYSA-N 4-amino-n-(1-azabicyclo[2.2.2]octan-3-yl)-3-chloro-5-(trifluoromethyl)benzamide Chemical compound C1=C(C(F)(F)F)C(N)=C(Cl)C=C1C(=O)NC1C(CC2)CCN2C1 UVJOFJBHOZFKQM-UHFFFAOYSA-N 0.000 description 1
- FVSJNUDCASWJPZ-WLHGVMLRSA-N 4-amino-n-(1-azabicyclo[2.2.2]octan-3-yl)-5-chloro-2-methoxybenzamide;(e)-but-2-enedioic acid Chemical compound OC(=O)\C=C\C(O)=O.COC1=CC(N)=C(Cl)C=C1C(=O)NC1C(CC2)CCN2C1 FVSJNUDCASWJPZ-WLHGVMLRSA-N 0.000 description 1
- DHKHMKIZOGIVPJ-WLHGVMLRSA-N 4-amino-n-(1-azabicyclo[2.2.2]octan-3-yl)-5-chloro-2-methoxybenzenecarbothioamide;(e)-but-2-enedioic acid Chemical compound OC(=O)\C=C\C(O)=O.COC1=CC(N)=C(Cl)C=C1C(=S)NC1C(CC2)CCN2C1 DHKHMKIZOGIVPJ-WLHGVMLRSA-N 0.000 description 1
- IGIGYPNZDJXGOS-UHFFFAOYSA-N 4-amino-n-(1-azabicyclo[2.2.2]octan-3-yl)benzamide Chemical compound C1=CC(N)=CC=C1C(=O)NC1C(CC2)CCN2C1 IGIGYPNZDJXGOS-UHFFFAOYSA-N 0.000 description 1
- TXJMYISJXPBNCC-UHFFFAOYSA-N 5-chloro-2-methoxy-4-(methylamino)benzoic acid Chemical compound CNC1=CC(OC)=C(C(O)=O)C=C1Cl TXJMYISJXPBNCC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 235000003911 Arachis Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 description 1
- 238000001061 Dunnett's test Methods 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 description 1
- 230000002082 anti-convulsion Effects 0.000 description 1
- 230000000026 anti-ulcerogenic effect Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 229940005530 anxiolytics Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- ZUDYPQRUOYEARG-UHFFFAOYSA-L barium(2+);dihydroxide;octahydrate Chemical compound O.O.O.O.O.O.O.O.[OH-].[OH-].[Ba+2] ZUDYPQRUOYEARG-UHFFFAOYSA-L 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- FXCLIEYDXXVEAI-UHFFFAOYSA-N benzene;dichloromethane Chemical compound ClCCl.C1=CC=CC=C1 FXCLIEYDXXVEAI-UHFFFAOYSA-N 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000008231 carbon dioxide-free water Substances 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229960000632 dexamfetamine Drugs 0.000 description 1
- 229960001149 dopamine hydrochloride Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- OYJXTOVLKZDGFK-UHFFFAOYSA-N ethanol;2-propan-2-yloxypropane Chemical compound CCO.CC(C)OC(C)C OYJXTOVLKZDGFK-UHFFFAOYSA-N 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 230000000574 ganglionic effect Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000002640 gastrokinetic effect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 1
- 229960003132 halothane Drugs 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- BLNWTAHYTCHDJH-UHFFFAOYSA-O hydroxy(oxo)azanium Chemical compound O[NH+]=O BLNWTAHYTCHDJH-UHFFFAOYSA-O 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 230000003137 locomotive effect Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- FAMJEZPAZMXBDI-UHFFFAOYSA-N n-(1-azabicyclo[2.2.2]octan-3-yl)-2,4-dimethoxybenzamide;hydrochloride Chemical compound Cl.COC1=CC(OC)=CC=C1C(=O)NC1C(CC2)CCN2C1 FAMJEZPAZMXBDI-UHFFFAOYSA-N 0.000 description 1
- BKHQZZSJCQSMPS-UHFFFAOYSA-N n-(1-azabicyclo[2.2.2]octan-3-yl)-2-propoxybenzamide;hydrochloride Chemical compound Cl.CCCOC1=CC=CC=C1C(=O)NC1C(CC2)CCN2C1 BKHQZZSJCQSMPS-UHFFFAOYSA-N 0.000 description 1
- PAGIBPYLPFBNHA-UHFFFAOYSA-N n-(1-azabicyclo[2.2.2]octan-3-yl)-3-methoxynaphthalene-2-carboxamide Chemical compound C1N(CC2)CCC2C1NC(=O)C1=CC2=CC=CC=C2C=C1OC PAGIBPYLPFBNHA-UHFFFAOYSA-N 0.000 description 1
- XCAYUNJSPOEITF-UHFFFAOYSA-N n-[(3-methoxyphenyl)methyl]-1-phenylmethanamine Chemical compound COC1=CC=CC(CNCC=2C=CC=CC=2)=C1 XCAYUNJSPOEITF-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- ITNXJLXLFAFOHO-UHFFFAOYSA-N n-piperidin-1-ylbenzamide Chemical class C=1C=CC=CC=1C(=O)NN1CCCCC1 ITNXJLXLFAFOHO-UHFFFAOYSA-N 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 150000008584 quinuclidines Chemical class 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 125000005624 silicic acid group Chemical class 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 239000004296 sodium metabisulphite Substances 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000007492 two-way ANOVA Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
Definitions
- the present invention relates to the use of certain N-(3-quinuclidinyl)benzamides and thiobenzamides, namely 2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)-benzamides and thiobenzamides which have been observed to exhibit antischizophrenic properties in warm blooded animals.
- substituted benzamides are a class of drugs known to be effective in psychiatry and gastroenterology (Sulpiride and other Benzamides; International Workshop on Sulpiride and other benzamides, Florence, Feb. 17-18 (1978), Raven Press].
- the 2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides used in this invention have now been found to have marked anxiolytic properties.
- EP-A-0158532 and FR-A-2529548 disclose the compounds useful in the present invention, but are concerned with activity on the gastrointestinal tract.
- FIG. 1. depicts a graph showing the antagonism by fluphenazine of the hyperactivity caused by dopamine infused bilaterally into the rat nucleus accumbens.
- dopamine control (25 ⁇ g/24 h). vehicle infusion.
- dopamine+fluphenazine 0.05 mg/kg b.d. n 6. **P ⁇ 0.01, ***P ⁇ 0.001, + P ⁇ 0.05, ++ P ⁇ 0.01, +++ P ⁇ 0.001 (two-way ANOVA followed by Dunnett's test).
- 2-Alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides and thiobenzamides used in this invention have the formula: ##STR2## wherein X represents oxygen or sulphur, R 1 represents loweralkyl and R 2 represents hydrogen, halo, 4,5-benzo, alkoxy or Am wherein Am represents amino, methylamino or dimethylamino, and n is 1 or 2, and the pharmaceutically acceptable acid addition salts thereof.
- loweralkyl as used herein includes straight and branched chain radicals of up to eight carbons inclusive and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, amyl, hexyl, heptyl, and octyl radicals and the like.
- loweralkyl has the formula --O--loweralkyl.
- halo or halogen when referred to herein include fluorine, chlorine, bromine and iodine unless otherwise stated.
- “Pharmaceutically acceptable acid addition salts” include the acid addition salts, hydrates, alcoholates and salts of the compounds, which salts are pysiologically compatible in warm blooded animals.
- the acid addition salts may be formed by either strong or weak acids.
- strong acids are hydrochloric, sulphuric and phosphoric acids.
- weak acids are fumaric, maleic, succinic, oxalic, citric, tartaric, cyclohexamic and the like.
- Protected amino groups used in synthesis are acetylamino or benzoylamino radicals and the like on the benzamide moiety mentioned hereinbelow in synthetic methods.
- the symptoms of schizophrenia have been associated, at least in part, with a raised mesolimbic dopamine function. This can be mimicked experimentally by infusing dopamine slowly and persistently into a mesolimbic area.
- dopamine was infused slowly and persistently into the nucleus accumbens of rat brain. This causes a hyperactivity which is neuroleptic sensitive.
- the dopamine infusion response is sensitive to antagonism by the above compounds which indicates an antischizophrenic potential for them.
- the antischizophrenic activity was determined by the method of Costall and Naylor, details of which are to be found in the pharmacology examples later in this specification.
- the method involves assessing the antagonism of hyperactivity of rats caused by dopamine infusion.
- a further object is to provide 2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl-benzamides and thiobenzamides having antischizophrenic properties.
- a still further object is to provide means for controlling schizophrenia.
- benzamido compounds of Formula I are prepared by reacting a suitably activated benzoic acid derivative with 3-aminoquinuclidine to form the corresponding benzamide under a variety of conditions.
- Two general methods, A and B, are illustrated in the following equations: ##STR3##
- R 2 is primary amino
- Methods A or B wherein R 2 is nitro by catalytic reduction of the nitro compound.
- compounds wherein R 2 is amino may be prepared by procedures of Method A utilizing a starting benzoyl halide wherein the amino group has been protected, or they may be prepared from compounds prepared in Method A or B wherein R 2 is nitro and reducing the nitro radical to an amino radical.
- the compounds wherein R 2 is amino or methylamino are prepared by Method B.
- the free base of any compound of Formula I from its acid addition salt may be regenerated by usual procedures of partitioning between dilute aqueous base and a suitable solvent, separating the solvent layer, drying and evaporating.
- the preparation of the thiobenzamido compounds of Formula II may be accomplished by mixing and reacting a benzamido compound of Formula I with a mixture of phosphorus pentasulphide (P 2 S 5 ) and potassium sulphide (K 2 S) or by mixing and reacting 3-aminoquinuclidine with an appropriately substituted benzaldehyde and sulphur.
- the reaction sequences are illustrated by the following: ##STR4## In these methods, compounds wherein R 2 is nitro may be reduced to compounds wherein R 2 is amino.
- a preferred group of compounds encompassed by Formula I have the formula: ##STR5## wherein Am is amino (i.e., --NH 2 ) or methylamino.
- the compounds are highly potent as gastric emptiers and as anti-emetics in conjunction with cisplatin cancer treatment, being more potent than metoclopramide and devoid of undesirable neuroleptic side effects even at much higher doses than required for their gastric emptying and antiemetic effects.
- these compounds (Ic) are preferably prepared by Method B.
- ammonium hydroxide solution in methanol showed some product formation.
- the mixture was heated at reflux temperature for 18 hours and then concentraded to an oil.
- TLC analysis showed the presence of the product, imidazole, and 3-aminoquinuclidine.
- the oil was dissolved in methylene chloride (75 ml) and washed twice with 50 ml portions of aqueous sodium bicarbonate solution. The methylene chloride layer was dried over anhydrous magnesium sulphate and concentrated to yield 2.0 g (67%) of a glassy amorphous solid, the free base of the title compound.
- ammonium hydroxide in methanol showed the free base to be pure.
- a solution of 1.17 g of the free base in 5 ml methanol was treated with a solution of 0.52 g fumaric acid in 10 ml methanol.
- Isopropyl ether was added to give approximately 100 ml of solution from which the fumarate salt precipitated.
- the salt was collected under nitrogen and dried in a vacuum oven at 60° C. overnight. NMR and elemental analyses showed that the product was a hemihydrate.
- the method of controlling schizophrenia in accordance with this invention comprises administering internally to warm blooded animals including human beings certain 2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides and thiobenzamides of Formula I, preferably Formula Ic, or a non-toxic organic or inorganic acid addition salt thereof in a wide variety of pharmaceutical forms well known in the art, preferably with a non-toxic pharmaceutical carrier such as is described below in an amount to control schizophrenia.
- the active agent is administered orally, subcutaneously, intravenously or intramuscularly or parenterally and, if necessary, in repeated doses until satisfactory response is obtained.
- Daily dosage regimes of the active agent will generally be such as to attain the dosages given below.
- the compounds may thus be presented in a therapeutic composition suitable for oral, parenteral, subcutaneous, intramuscular, intraperitoneal or intravenous administration.
- compositions for oral administration can take the form of elixirs, capsules, tablets or coated tablets containing carriers conveniently used in the pharmaceutical art.
- Exemplary of solid carriers including tableting and capsulating excipients are lactose, sucrose, potato and maize starches, talc, gelatin, agar, pectin or acacia, stearic and silicic acids, magnesium stearate, terra alba and polyvinyl pyrrolidone.
- the carrier or excipient can be comprised of a sterile parenterally acceptable liquid; e.g. water or arachis oil contained in ampoules.
- the pharmaceutical compositions may be formulated to contain from about 5 ng/kg to about 10 mcg/kg body weight, preferably 1 mcg/kg body weight or less. It will generally be the case that the dose will be less than 0.2-2.0 mg/kg per day as a loss of selectivity of action may result. It is necessary that the active ingredient of Formula I constitute an effective amount.
- FIG. 1 shows antagonism by fluphenazine of hyperactivity caused by dopamine infused bilaterally into the rat nucleus accumbens
- FIG. 2 shows the ability of the compound of Example 1 to antagonise a raised mesolimbic dopamine activity
- FIG. 3 shows the ability of the compound of Example 1 to antagonise a raised mesolimbic dopamine hyperactivity.
- the behavioural measure throughout was hyperactivity assessed in individual photocell cages constructed of perspex, 25 ⁇ 15 ⁇ 15 cm high, each fitted with one photocell unit placed off-centre. The cages were screened. Interruptions of the light beams were continuously monitored and the level of locomotor activity expressed in counts/5 min.
- Rats were subject to standard stereotaxic techniques for the implantation of chronically indwelling guide cannulae for subsequent bilateral intracerebral infusion into the centre of the nucleus accumbens (Ant. 9.4, Vert. 0.0, Lat. ⁇ 1.6, atlas of De Groot). Rats were anaesthetised with chloral hydrate (300 mg/kg s.c.) and placed in a Kopf stereotaxic instrument. Implanted guides were constructed of stainless steel, 0.65 mm diameter, held bilaterally in perspex holders. Guides terminated 3.5 mm above the centre of the nucleus accumbens and were kept patent for a 14-day recovery period using stainless steel stylets extending 0.5 mm beyond the guide tips.
- the pumps had previously been filled with dopamine solution (2.17 mcg/mcl, dopamine hydrochloride, Koch Light, prepared in N 2 bubbled solution containing 0.1% sodium metabisulphite), or its solvent, and the entire injection unit primed for between 5 and 8 hr at 37° C.
- the pumps delivered dopamine or its solvent at a constant rate of 0.48 mcl/hr from the time of implantation, and thus provided an intra-accumbens dose of dopamine of 25 mcg over a 24 hr period. Pumps were removed on day 13. Rat spontaneous locomotion was measured between 8.00 and 11.00 am.
- the compound of Example 1 ("Compound 1") and fluphenazine were given twice daily at 7.30 am and 7.30 pm.
- the hyperactivity caused by dopamine infusion into the nucleus accumbens of rat was antagonised by the classical neuroleptic agent fluphenazine at doses of 0.025-0.05 mg/kg given twice daily.
- fluphenazine treatment At the highest dose of 0.05 mg/kg the fluphenazine treatment not only suppressed the dopamine response but caused clear motor depression to values below control (FIG. 1).
- both the dopamine infusion and the fluphenazine treatment were stopped, and in those rats where the fluphenazine had successfully suppressed the dopamine hyperactivity a marked rebound hyperactivity developed which persisted in excess of 21 days (FIG. 1).
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Neurology (AREA)
- Organic Chemistry (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims (8)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8720805 | 1987-09-04 | ||
GB878720805A GB8720805D0 (en) | 1987-09-04 | 1987-09-04 | 2-alkoxy-n-(1-azabicyclo(2 2 2)oct-3-yl)benzamides & thiobenzamides |
Publications (1)
Publication Number | Publication Date |
---|---|
US4877794A true US4877794A (en) | 1989-10-31 |
Family
ID=10623261
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US07/240,868 Expired - Fee Related US4877794A (en) | 1987-09-04 | 1988-09-06 | 2-Alkoxy-n-(1-azabicyclo(2.2.2)oct-3-yl) benzamide and thiobenzamide compositions and the use thereof to treat schizophrenia |
Country Status (12)
Country | Link |
---|---|
US (1) | US4877794A (en) |
EP (1) | EP0306345B1 (en) |
JP (1) | JPH0269417A (en) |
AT (1) | ATE88091T1 (en) |
AU (1) | AU614768B2 (en) |
CA (1) | CA1318595C (en) |
DE (1) | DE3880240T2 (en) |
DK (1) | DK492688A (en) |
GB (1) | GB8720805D0 (en) |
IL (1) | IL87662A0 (en) |
PH (1) | PH25429A (en) |
ZA (1) | ZA886586B (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5025022A (en) * | 1988-08-04 | 1991-06-18 | Naylor Robert J | Method of treating or preventing schizophrenia and/or psychosis using S-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides and thiobenzamides |
US6479510B2 (en) | 2000-08-18 | 2002-11-12 | Pharmacia & Upjohn Company | Quinuclidine-substituted aryl compounds for treatment of disease |
US6486172B2 (en) | 2000-08-18 | 2002-11-26 | Pharmacia & Upjohn Company | Quinuclidine-substituted aryl compounds for treatment of disease |
US20030069296A1 (en) * | 2001-08-24 | 2003-04-10 | Wishka Donn G. | Substituted-aryl 7-aza[2.2.1]bicycloheptanes for the treatment of disease |
US20030236270A1 (en) * | 2002-02-20 | 2003-12-25 | Jacobsen Eric Jon | Azabicyclic compounds for the treatment of disease |
US6852716B2 (en) | 2002-02-15 | 2005-02-08 | Pfizer Inc | Substituted-aryl compounds for treatment of disease |
US20100022548A1 (en) * | 2003-10-17 | 2010-01-28 | Sanofi-Aventis | Use of n-heterocyclylmethylbenzamides in therapeutics |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1990012569A1 (en) * | 1989-04-21 | 1990-11-01 | Sandoz Ag | Therapeutic use of 5-ht3 receptor antagonists |
US5236931A (en) * | 1992-03-26 | 1993-08-17 | A. H. Robins Company, Incorporated | 2-substituted benzamide and benzoate derivatives of 3-aminoquinuclidine and 3-quinuclidinol |
US8435762B2 (en) | 2008-10-09 | 2013-05-07 | Howard Hughes Medical Institute | Chimeric ligand-gated ion channels and methods of use thereof |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4093734A (en) * | 1975-11-03 | 1978-06-06 | Boehringer Ingelheim Gmbh | Amino-benzoic acid amides |
EP0099789A1 (en) * | 1982-07-02 | 1984-02-01 | Delalande S.A. | 3-Aminoquinuclidin derivatives, process for their preparation and their use as therapeutical agents |
GB2125398A (en) * | 1982-06-29 | 1984-03-07 | Sandoz Ltd | Bridged piperidyl esters and amides |
EP0158532A2 (en) * | 1984-04-06 | 1985-10-16 | Synthelabo | Use of 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide for the manufacture of a medicament having anti-emetic activity. |
EP0201165A2 (en) * | 1985-03-14 | 1986-11-12 | Beecham Group Plc | Medicaments for the treatment of emesis |
EP0202062A2 (en) * | 1985-05-11 | 1986-11-20 | Beecham Group Plc | Quinuclidine derivatives |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4605652A (en) * | 1985-02-04 | 1986-08-12 | A. H. Robins Company, Inc. | Method of enhancing memory or correcting memory deficiency with arylamido (and arylthioamido)-azabicycloalkanes |
PH23937A (en) * | 1986-12-16 | 1990-01-23 | Robins Co Inc A H | Anxiolytic-n-(1-azabicyclo(2.2.2.)oct-3-yl)benzamides and thiobenzamides |
-
1987
- 1987-09-04 GB GB878720805A patent/GB8720805D0/en active Pending
-
1988
- 1988-09-02 IL IL87662A patent/IL87662A0/en unknown
- 1988-09-05 PH PH37505A patent/PH25429A/en unknown
- 1988-09-05 EP EP88308182A patent/EP0306345B1/en not_active Expired - Lifetime
- 1988-09-05 DE DE88308182T patent/DE3880240T2/en not_active Expired - Fee Related
- 1988-09-05 JP JP63220559A patent/JPH0269417A/en active Pending
- 1988-09-05 AU AU21834/88A patent/AU614768B2/en not_active Ceased
- 1988-09-05 AT AT88308182T patent/ATE88091T1/en not_active IP Right Cessation
- 1988-09-05 ZA ZA886586A patent/ZA886586B/en unknown
- 1988-09-05 DK DK492688A patent/DK492688A/en not_active Application Discontinuation
- 1988-09-06 US US07/240,868 patent/US4877794A/en not_active Expired - Fee Related
- 1988-09-06 CA CA000576593A patent/CA1318595C/en not_active Expired - Fee Related
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4093734A (en) * | 1975-11-03 | 1978-06-06 | Boehringer Ingelheim Gmbh | Amino-benzoic acid amides |
GB2125398A (en) * | 1982-06-29 | 1984-03-07 | Sandoz Ltd | Bridged piperidyl esters and amides |
EP0099789A1 (en) * | 1982-07-02 | 1984-02-01 | Delalande S.A. | 3-Aminoquinuclidin derivatives, process for their preparation and their use as therapeutical agents |
EP0158532A2 (en) * | 1984-04-06 | 1985-10-16 | Synthelabo | Use of 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide for the manufacture of a medicament having anti-emetic activity. |
US4593034A (en) * | 1984-04-06 | 1986-06-03 | A. H. Robins Company, Inc. | 2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides and thiobenzamides |
EP0201165A2 (en) * | 1985-03-14 | 1986-11-12 | Beecham Group Plc | Medicaments for the treatment of emesis |
EP0202062A2 (en) * | 1985-05-11 | 1986-11-20 | Beecham Group Plc | Quinuclidine derivatives |
Non-Patent Citations (4)
Title |
---|
Krueger, G. et al., Chem. Abstr. 87:68001(c) (1977). * |
Mikhlina et al., Chem. Abstr. 65:2220b (1966). * |
Mikhlina et al., Chem. Abstr. 79:146358a (1973). * |
Mikhlina et al., Chem. Abstr. 86:155489r (1977). * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5025022A (en) * | 1988-08-04 | 1991-06-18 | Naylor Robert J | Method of treating or preventing schizophrenia and/or psychosis using S-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides and thiobenzamides |
US6479510B2 (en) | 2000-08-18 | 2002-11-12 | Pharmacia & Upjohn Company | Quinuclidine-substituted aryl compounds for treatment of disease |
US6486172B2 (en) | 2000-08-18 | 2002-11-26 | Pharmacia & Upjohn Company | Quinuclidine-substituted aryl compounds for treatment of disease |
US20030069296A1 (en) * | 2001-08-24 | 2003-04-10 | Wishka Donn G. | Substituted-aryl 7-aza[2.2.1]bicycloheptanes for the treatment of disease |
US6852716B2 (en) | 2002-02-15 | 2005-02-08 | Pfizer Inc | Substituted-aryl compounds for treatment of disease |
US20030236270A1 (en) * | 2002-02-20 | 2003-12-25 | Jacobsen Eric Jon | Azabicyclic compounds for the treatment of disease |
US7001900B2 (en) | 2002-02-20 | 2006-02-21 | Pfizer Inc. | Azabicyclic compounds for the treatment of disease |
US20100022548A1 (en) * | 2003-10-17 | 2010-01-28 | Sanofi-Aventis | Use of n-heterocyclylmethylbenzamides in therapeutics |
US8513246B2 (en) | 2003-10-17 | 2013-08-20 | Sanofi | Use of N-heterocyclylmethylbenzamides in therapeutics |
Also Published As
Publication number | Publication date |
---|---|
ZA886586B (en) | 1990-05-30 |
AU2183488A (en) | 1989-03-09 |
EP0306345A3 (en) | 1989-06-14 |
ATE88091T1 (en) | 1993-04-15 |
DK492688A (en) | 1989-03-05 |
AU614768B2 (en) | 1991-09-12 |
GB8720805D0 (en) | 1987-10-14 |
IL87662A0 (en) | 1989-02-28 |
EP0306345B1 (en) | 1993-04-14 |
DK492688D0 (en) | 1988-09-05 |
EP0306345A2 (en) | 1989-03-08 |
JPH0269417A (en) | 1990-03-08 |
DE3880240T2 (en) | 1993-10-28 |
DE3880240D1 (en) | 1993-05-19 |
PH25429A (en) | 1991-07-01 |
CA1318595C (en) | 1993-06-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4593034A (en) | 2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides and thiobenzamides | |
US4908370A (en) | Anxiolytic-n-(1-azabicyclo(2.2.2)oct-3-yl) benzamides and thiobenzamides | |
EP0190920B1 (en) | Method of enhancing memory or correcting memory deficiency with arylamido (and arylthioamido)azabicycloalkanes | |
US4717563A (en) | 2-alkoxy-N-(1-azabicyclo(2.2.2)oct-3-yl) benzamides and thiobenzamides in a method for alleviating emesis caused by non-platinum anticancer drugs | |
US5084460A (en) | Methods of therapeutic treatment with N-(3-ouinuclidinyl)-2-hydroxybenzamides and thiobenzamides | |
IE47798B1 (en) | Substituted ortho-anisamides,methods of preparing them,compositions containing them and their application as psychotropic agents | |
EP0353372B1 (en) | Antischizophrenic-S-N-(1-azabicyclo[2.2.2.]oct-3-yl) benzamides and thiobenzamides | |
EP0353371A1 (en) | Memory enhancing-R-N-(1-azabicyclo[2.2.2] oct-3-yl) benzamides and thiobenzamides | |
RU2139288C1 (en) | Imidazo[1,2-a]pyridine alkoxyalkylcarbamates and drug based on said | |
US4877794A (en) | 2-Alkoxy-n-(1-azabicyclo(2.2.2)oct-3-yl) benzamide and thiobenzamide compositions and the use thereof to treat schizophrenia | |
US5206246A (en) | Anxiolytic-R-n(1-azabicyclo[2.2.2]oct-3-yl) benzamides and thiobenzamides | |
US4722834A (en) | Method of using 2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide-N-oxides to control emesis caused by anticancer drugs | |
AU618027B2 (en) | Anxiolytic-r-n-(1-azabicyclo(2.2.2)oct-3-yl) benzamides and thiobenzamides | |
US5202325A (en) | Use of ergoline derivatives in treating emesis | |
US3483294A (en) | 1,1-diethyl-2-methyl - 3 - diphenylmethylenepyrrolidinium halide compositions and therapy | |
US3856963A (en) | Use of injectable compositions of the ({30 )-optional isomer of the alpha racemate of 2-(2-ethyl-2-phenyl-1,3-dioxolan-4-yl) piperidine to control pain | |
JP3681770B2 (en) | Treatment for senile dementia or Alzheimer's disease | |
JPS63215678A (en) | Antianxiety n-(1-azabicyclo(2,2,2)-3-octyl) benzamide and thiobenzamide |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: A. H. ROBINS COMPANY, INCORPORATED Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:NAYLOR, ROBERT J.;NAYLOR, BRENDA;REEL/FRAME:005023/0497 Effective date: 19881222 |
|
FEPP | Fee payment procedure |
Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
AS | Assignment |
Owner name: A.H. ROBINS COMPANY, INCORPORATED, A DE CORP. Free format text: CHANGE OF NAME;ASSIGNOR:A.H. ROBINS COMPANY, INCORPORATED, A CORP. OF VA (INTO);REEL/FRAME:005587/0178 Effective date: 19891213 |
|
AS | Assignment |
Owner name: AHP SUBSIDIARY CORPORATION A CORPORATION OF DEL Free format text: MERGER;ASSIGNOR:A.H. ROBINS COMPANY, ICNORPORATED, A CORP. OF VA;REEL/FRAME:005945/0199 Effective date: 19891213 |
|
FEPP | Fee payment procedure |
Free format text: PAYER NUMBER DE-ASSIGNED (ORIGINAL EVENT CODE: RMPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
FEPP | Fee payment procedure |
Free format text: PAYER NUMBER DE-ASSIGNED (ORIGINAL EVENT CODE: RMPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
FPAY | Fee payment |
Year of fee payment: 4 |
|
REMI | Maintenance fee reminder mailed | ||
LAPS | Lapse for failure to pay maintenance fees | ||
FP | Lapsed due to failure to pay maintenance fee |
Effective date: 19971105 |
|
STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |